Islet transplantation for a sustainable cure for type 1 diabetes - all they need is the air that they breathe1st Dec 2014Case Study: James Shaw, Professor of Regenerative Medicine for Diabetes, Newcastle University
Transplantation of insulin secreting pancreatic islets from deceased organ donors is established within the NHS as a successful and sustainable cell therapy for longstanding type 1 diabetes complicated by recurrent life threatening low glucose reactions (hypoglycaemia).
It is often stated that the limiting factor for cell transplantation for diabetes is insufficient beta cells justifying the need for novel stem cell derived sources. There are, however, sufficient organ donors under the age of 60 years to transplant all of the patients on the current UK islet transplant waiting list every year.
In reality there are two major factors preventing provision of this regenerative medicine therapy to the 300,000 people with type 1 diabetes in the UK:
1. Inability to reproducibly deliver sustainable insulin independence from a single minimally invasive transplant procedure.
2. Need for toxic lifelong immunosuppression to prevent rejection of the foreign graft and recurrent diabetic autoimmune attack.
A single transplant should be more than enough but 50% of transplanted islets are irreversibly damaged through oxygen starvation and lost over the first week before they can re-establish a blood supply from the transplant site in the liver. In the native pancreas, islets rely on a particularly dense network of blood vessels being absolutely dependent on an uninterrupted oxygen supply. Donor death severs the connection to the circulatory network leaving the core of these islands of tissue without oxygen until new blood vessels grow following transplantation.
In Newcastle we are exploring a range of innovative approaches to limit islet hypoxia during all bioprocessing steps:
Pancreas persufflation bubbles oxygen through the vasculature following organ retrieval. The goal is to maintain islet viability and metabolic health while the organ is transported to the islet isolation facility. Underpinned by persuasive proof of concept data and in collaboration with Dr Klearchos Papas at University of Arizona, we propose a national randomised controlled trial comparing persufflation with standard pancreas preservation in all organs offered for clinical transplantation in the UK.
Following isolation, islets are maintained in standard suspension culture and may subsequently require transport to a distant transplant centre. As a cluster of cells which may be up to 0.5 mm in diameter, oxygen limitation within the core often leads to central necrosis, inducing an instant inflammatory response post-transplantation leading to a major loss of functional mass. We are exploring a range of novel bioreactor approaches aimed at maximising islet health and oxygenation post-isolation and pre-transplantation.
Ischaemia persists for many days post-transplantation through the requirement for development of a new host derived vascular network at the site of transplantation. Working with collaborators in Israel, we are currently exploring ex vivo combination of islets with recipient derived blood cells enriched for endothelial progenitor cells to facilitate revascularisation post-transplantation, minimising hypoxic stress and maximising engrafted transplant mass.
Immunobarrier encapsulation of islets promises transplantation without the need for systemic immunosuppressive drugs, thus avoiding the associated risk of severe infections and malignancy.
An effective barrier also prevents islet revascularisation and is thus associated with necrotic cell death. In situ oxygenation provides a potential solution. This is currently being pioneered through subcutaneous transplantation of islets within a macro-encapsulation device which is then injected percutaneously with oxygen.
Overall it is envisaged that transformative enhancement of clinical transplant outcomes will be achieved in the near future through a range of innovations targeting and attenuating islet hypoxia.
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